The Aspirin Paradox, Unraveled

Originally developed in 1897 as a painkiller, aspirin has become a valuable cardiology tool in the 21st century for preventing and treating cardiovascular disease. Because of the drug’s ability to reduce blood clotting, doctors commonly recommend a daily aspirin to patients at high risk or with a history of heart attacks, strokes, and other cardiovascular ailments. Extensive research has largely supported the drug as a cheap and effective way to prevent these life-threatening events and to help nullify what remains the leading cause of death in the United States.

But in 2000, a group of Boston cardiologists trying to identify risk factors that might predict poor outcomes after a heart attack made a strange discovery. Most of the predictive risk factors they discovered and ultimately incorporated into their well-known 7-point “TIMI risk score” made perfect sense. For example, if you came to the emergency room with chest pain and had an abnormal electrocardiogram or elevated levels in the blood signaling heart damage, you were more likely to be at risk for future adverse events. But the team also discovered one risk factor for predicting worse outcomes that was far from expected: the prior use of aspirin. According to their analysis, patients who were taking aspirin to prevent cardiovascular disease actually did worse after suffering a heart attack.

“It seemed to make little sense, because aspirin had clearly proven itself in other settings to be protective against heart attacks,” said Jonathan Rich, an instructor of medicine in the section of cardiology at the University of Chicago Medical Center. “If you suffered a heart attack, to prevent you from having another, your doctor invariably puts you on aspirin. So this unexpected discovery caught everyone’s attention. Did this mean that aspirin use could actually be hurting people?”

Dubbed the “aspirin paradox,” this observation did not deter doctors from continuing to prescribe aspirin for the prevention of cardiovascular disease. But the mystery caused some to wonder whether there was a biological reason for aspirin’s unexpected role as a risk factor, such as “aspirin resistance” in some patients, or if there was instead an epidemiological or statistical explanation. While working in Boston with the TIMI study group, Rich took charge of an effort to comb through the data for a way to explain the paradox.

The research ultimately led to a study, published last month in the Journal of the American College of Cardiology, which seems to take aspirin off the hook. When researchers controlled for a long list of potential confounding variables such as age, sex, smoking, and previous history of cardiovascular events, the association of prior aspirin use with a higher chance of post-event mortality entirely disappeared. Aspirin, they concluded, was not directly causing worse outcomes after a heart attack. Instead, it was simply a common drug that people with previous cardiovascular disease – by definition, a population at high risk for poorer outcomes, were frequently taking.

“Aspirin is probably an innocent bystander,” Rich said. “The reason people who take aspirin do worse than those not taking aspirin is because those taking aspirin have already suffered a heart attack, a stroke, or have heart failure for which they were prescribed the drug. In actuality, when we looked closer at the heart attacks that people suffered, those who were taking aspirin actually had less severe heart attacks than those not taking aspirin, suggesting that perhaps aspirin was indeed beneficial, but simply insufficient to prevent the heart attack entirely.”

That doesn’t mean prior aspirin use loses its status as a warning sign for adverse outcomes after a heart attack, Rich said. While the drug may not be directly responsible for the increased risk of “badness” after a cardiac event, it’s still a good predictor of who might need more aggressive care when they show up in the emergency room with chest pain. So, while the aspirin paradox loses some of its mystery, aspirin use lives on as a useful marker for physicians.

“In some ways, if all I am told is that there is a patient with chest pain and he or she is taking aspirin, I can safely conclude that the individual is likely at increased risk for adverse events and should thus be treated aggressively,” Rich said. “Prior aspirin use remains a very reliable marker of a cohort of patients at high risk of bad outcomes, and that is really what a risk score is supposed to do – help stratify patients into high and low risk groups. We can thus continue to use aspirin as a signal to identify the high risk patients.”